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D-Serine Can Modify the Wall Teichoic Acid of MRSA via the dlt Pathway
Lei Wang1,2, Jinru Xie1,2, Qing Wang3
1Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Abstract:
Methicillin-resistant Staphylococcus aureus (MRSA) infection is a serious clinical threat, and D-Serine (D-Ser) showed significant sensitization effects on β-lactams against MRSA in our previous study. Quantitative PCR analysis found the elevated expression of the dlt operon with D-Ser combination, which is responsible for wall teichoic acid (WTA) modification involving D-Alanine (D-Ala). This study aims to verify the effect of D-Ser on WTA modification through the dlt pathway and explore the related effects on bacteria. The DltA and DltC were recombined, and enzyme kinetic evaluations with different D-amino acids were then conducted; it was found that D-Ser is the second-best substrate for DltA (just after D-Ala), no matter whether DltC is present or not. D-Ser treatment also lowered WTA generation as demonstrated by WTA phosphate quantification and native-PAGE electrophoresis, increased the susceptibility of S. aureus to polymyxins, and elevated the mouse survival rate in the MRSA intraperitoneal infection model without affecting the bacterial loads in the main organs, indicating possible effects of D-Ser on MRSA virulence through WTA modification. In conclusion, the current study provided evidence for D-Ser modification of WTA via the dlt pathway, and its possible involvement in D-Ser sensitization deserves further investigation.
Insights
D-Serine (D-Ser) modifies Staphylococcus aureus wall teichoic acid (WTA) via the dlt pathway. This D-Serine effect enhances antibiotic sensitivity and improves survival in MRSA infections.
Area of Science:
- Microbiology
- Biochemistry
- Infectious Diseases
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant clinical challenge.
- D-Serine (D-Ser) previously demonstrated sensitization of beta-lactams against MRSA.
- Elevated dlt operon expression, responsible for wall teichoic acid (WTA) modification, was observed with D-Ser.
Purpose of the Study:
- To verify D-Serine's effect on WTA modification through the dlt pathway.
- To explore the impact of D-Serine on bacterial properties and virulence.
- To investigate the mechanism behind D-Serine's sensitization of MRSA.
Main Methods:
- Recombination of DltA and DltC enzymes for kinetic evaluations.
- Enzyme kinetic assays using various D-amino acids as substrates.
- Quantification of WTA phosphate and native-PAGE electrophoresis to assess WTA generation.
- Assessment of S. aureus susceptibility to polymyxins.
- Evaluation of mouse survival rates in an MRSA intraperitoneal infection model.
Main Results:
- D-Serine was identified as the second-best substrate for DltA, following D-Alanine (D-Ala).
- D-Serine treatment reduced WTA generation in S. aureus.
- Increased susceptibility of S. aureus to polymyxins was observed.
- Mouse survival rates improved in the MRSA infection model without altered bacterial organ loads.
Conclusions:
- D-Serine modifies Staphylococcus aureus WTA via the dlt pathway.
- D-Serine's influence on WTA is linked to increased antibiotic susceptibility and improved outcomes in MRSA infections.
- Further investigation into D-Serine's role in MRSA sensitization is warranted.
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